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Neurobiology of Disease Mar 2024Stress disorders are psychiatric disorders arising following stressful or traumatic events. They could deleteriously affect an individual's health because they often... (Review)
Review
Stress disorders are psychiatric disorders arising following stressful or traumatic events. They could deleteriously affect an individual's health because they often co-occur with mental illnesses. Considerable attention has been focused on neurons when considering the neurobiology of stress disorders. However, like other mental health conditions, recent studies have highlighted the importance of astrocytes in the pathophysiology of stress-related disorders. In addition to their structural and homeostatic support role, astrocytes actively serve several functions in regulating synaptic transmission and plasticity, protecting neurons from toxic compounds, and providing metabolic support for neurons. The astrocyte-neuron lactate shuttle model sets forth the importance of astrocytes in providing lactate for the metabolic supply of neurons under intense activity. Lactate also plays a role as a signaling molecule and has been recently studied regarding its antidepressant activity. This review discusses the involvement of astrocytes and brain energy metabolism in stress and further reflects on the importance of lactate as an energy supply in the brain and its emerging antidepressant role in stress-related disorders.
Topics: Humans; Lactic Acid; Astrocytes; Glucose; Energy Metabolism; Antidepressive Agents
PubMed: 38296112
DOI: 10.1016/j.nbd.2024.106417 -
Frontiers in Synaptic Neuroscience 2023
PubMed: 37560131
DOI: 10.3389/fnsyn.2023.1254416 -
ACS Chemical Neuroscience Apr 2024Serotonin (5-HT) is a vital modulatory neurotransmitter responsible for regulating most behaviors in the brain. An inefficient 5-HT synaptic function is often linked to... (Review)
Review
Serotonin (5-HT) is a vital modulatory neurotransmitter responsible for regulating most behaviors in the brain. An inefficient 5-HT synaptic function is often linked to various mental disorders. Primarily, membrane proteins controlling the expression and activity of 5-HT synthesis, storage, release, receptor activation, and inactivation are critical to 5-HT signaling in synaptic and extra-synaptic sites. Moreover, these signals represent information transmission across membranes. Although the lipid membrane environment is often viewed as fairly stable, emerging research suggests significant functional lipid-protein interactions with many synaptic 5-HT proteins. These protein-lipid interactions extend to almost all the primary lipid classes that form the plasma membrane. Collectively, these lipid classes and lipid-protein interactions affect 5-HT synaptic efficacy at the synapse. The highly dynamic lipid composition of synaptic membranes suggests that these lipids and their interactions with proteins may contribute to the plasticity of the 5-HT synapse. Therefore, this broader protein-lipid model of the 5-HT synapse necessitates a reconsideration of 5-HT's role in various associated mental disorders.
Topics: Humans; Serotonin; Signal Transduction; Synapses; Cell Membrane; Lipids; Synaptic Transmission
PubMed: 38499042
DOI: 10.1021/acschemneuro.3c00823 -
Science Advances Nov 2023Synaptic plasticity plays a crucial role in memory formation by regulating the communication between neurons. Although actin polymerization has been linked to synaptic...
Synaptic plasticity plays a crucial role in memory formation by regulating the communication between neurons. Although actin polymerization has been linked to synaptic plasticity and dendritic spine stability, the causal link between actin polymerization and memory encoding has not been identified yet. It is not clear whether actin polymerization and structural changes in dendritic spines are a driver or a consequence of learning and memory. Using an extrinsically disordered form of the protein kinase LIMK1, which rapidly and precisely acts on ADF/cofilin, a direct modifier of actin, we induced long-term enlargement of dendritic spines and enhancement of synaptic transmission in the hippocampus on command. The activation of extrinsically disordered LIMK1 in vivo improved memory encoding and slowed cognitive decline in aged mice exhibiting reduced cofilin phosphorylation. The engineered memory by an extrinsically disordered LIMK1 supports a direct causal link between actin-mediated synaptic transmission and memory.
Topics: Mice; Animals; Actins; Hippocampus; Actin Depolymerizing Factors; Phosphorylation; Neuronal Plasticity
PubMed: 37967196
DOI: 10.1126/sciadv.adh1110 -
International Journal of Molecular... May 2024Dopamine is a key neurotransmitter involved in physiological processes such as motor control, motivation, reward, cognitive function, and maternal and reproductive... (Review)
Review
Dopamine is a key neurotransmitter involved in physiological processes such as motor control, motivation, reward, cognitive function, and maternal and reproductive behaviors. Therefore, dysfunctions of the dopaminergic system are related to a plethora of human diseases. Dopamine, via different circuitries implicated in compulsive behavior, reward, and habit formation, also represents a key player in substance use disorder and the formation and perpetuation of mechanisms leading to addiction. Here, we propose dopamine as a model not only of neurotransmission but also of neuromodulation capable of modifying neuronal architecture. Abuse of substances like methamphetamine, cocaine, and alcohol and their consumption over time can induce changes in neuronal activities. These modifications lead to synaptic plasticity and finally to morphological and functional changes, starting from maladaptive neuro-modulation and ending in neurodegeneration.
Topics: Humans; Dopamine; Animals; Substance-Related Disorders; Neuronal Plasticity; Synaptic Transmission
PubMed: 38791331
DOI: 10.3390/ijms25105293 -
Frontiers in Cellular Neuroscience 2023At the end of the 20th century, analog systems in computer science have been widely replaced by digital systems due to their higher computing power. Nevertheless, the... (Review)
Review
At the end of the 20th century, analog systems in computer science have been widely replaced by digital systems due to their higher computing power. Nevertheless, the question keeps being intriguing until now: is the brain analog or digital? Initially, the latter has been favored, considering it as a Turing machine that works like a digital computer. However, more recently, digital and analog processes have been combined to implant human behavior in robots, endowing them with artificial intelligence (AI). Therefore, we think it is timely to compare mathematical models with the biology of computation in the brain. To this end, digital and analog processes clearly identified in cellular and molecular interactions in the Central Nervous System are highlighted. But above that, we try to pinpoint reasons distinguishing computation from salient features of biological computation. First, genuinely analog information processing has been observed in electrical synapses and through gap junctions, the latter both in neurons and astrocytes. Apparently opposed to that, neuronal action potentials (APs) or spikes represent clearly digital events, like the yes/no or 1/0 of a Turing machine. However, spikes are rarely uniform, but can vary in amplitude and widths, which has significant, differential effects on transmitter release at the presynaptic terminal, where notwithstanding the quantal (vesicular) release itself is digital. Conversely, at the dendritic site of the postsynaptic neuron, there are numerous analog events of computation. Moreover, synaptic transmission of information is not only neuronal, but heavily influenced by astrocytes tightly ensheathing the majority of synapses in brain (tripartite synapse). At least at this point, LTP and LTD modifying synaptic plasticity and believed to induce short and long-term memory processes including consolidation (equivalent to RAM and ROM in electronic devices) have to be discussed. The present knowledge of how the brain stores and retrieves memories includes a variety of options (e.g., neuronal network oscillations, engram cells, astrocytic syncytium). Also epigenetic features play crucial roles in memory formation and its consolidation, which necessarily guides to molecular events like gene transcription and translation. In conclusion, brain computation is not only digital or analog, or a combination of both, but encompasses features in parallel, and of higher orders of complexity.
PubMed: 37608987
DOI: 10.3389/fncel.2023.1220030 -
Cell Reports Jul 2023An abnormal glutamate signaling pathway has been proposed in the mechanisms of autism spectrum disorder (ASD). However, less is known about the involvement of...
An abnormal glutamate signaling pathway has been proposed in the mechanisms of autism spectrum disorder (ASD). However, less is known about the involvement of alterations of glutaminase 1 (GLS1) in the pathophysiology of ASD. We show that the transcript level of GLS1 is significantly decreased in the postmortem frontal cortex and peripheral blood of ASD subjects. Mice lacking Gls1 in CamKIIα-positive neurons display a series of ASD-like behaviors, synaptic excitatory and inhibitory (E/I) imbalance, higher spine density, and glutamate receptor expression in the prefrontal cortex, as well as a compromised expression pattern of genes involved in synapse pruning and less engulfed synaptic puncta in microglia. A low dose of lipopolysaccharide treatment restores microglial synapse pruning, corrects synaptic neurotransmission, and rescues behavioral deficits in these mice. In summary, these findings provide mechanistic insights into Gls1 loss in ASD symptoms and identify Gls1 as a target for the treatment of ASD.
Topics: Mice; Animals; Autism Spectrum Disorder; Glutaminase; Neurons; Synaptic Transmission; Prefrontal Cortex; Disease Models, Animal
PubMed: 37384529
DOI: 10.1016/j.celrep.2023.112712 -
Frontiers in Cell and Developmental... 2023Neuromuscular junctions (NMJs) are a special type of chemical synapse that transmits electrical stimuli from motor neurons (MNs) to their innervating skeletal muscle to... (Review)
Review
Neuromuscular junctions (NMJs) are a special type of chemical synapse that transmits electrical stimuli from motor neurons (MNs) to their innervating skeletal muscle to induce a motor response. They are an ideal model for the study of synapses, given their manageable size and easy accessibility. Alterations in their morphology or function lead to neuromuscular disorders, such as the congenital myasthenic syndromes, which are caused by mutations in proteins located in the NMJ. In this review, we highlight novel potential candidate genes that may cause or modify NMJs-related pathologies in humans by exploring the phenotypes of hundreds of mouse models available in the literature. We also underscore the fact that NMJs may differ between species, muscles or even sexes. Hence the importance of choosing a good model organism for the study of NMJ-related diseases: only taking into account the specific features of the mammalian NMJ, experimental results would be efficiently translated to the clinic.
PubMed: 37601107
DOI: 10.3389/fcell.2023.1216726 -
Molecular Brain Jan 2024O-GlcNAcylation is a posttranslational modification where N-acetylglucosamine (O-GlcNAc) is attached and detached from a serine/threonine position by two enzymes:... (Review)
Review
O-GlcNAcylation is a posttranslational modification where N-acetylglucosamine (O-GlcNAc) is attached and detached from a serine/threonine position by two enzymes: O-GlcNAc transferase and O-GlcNAcase. In addition to roles in diabetes and cancer, recent pharmacological and genetic studies have revealed that O-GlcNAcylation is involved in neuronal function, specifically synaptic transmission. Global alteration of the O-GlcNAc level does not affect basal synaptic transmission while the effect on synaptic plasticity is unclear. Although synaptic proteins that are O-GlcNAcylated are gradually being discovered, the mechanism of how O-GlcNAcylated synaptic protein modulate synaptic transmission has only been reported on CREB, synapsin, and GluA2 subunit of AMPAR. Future research enabling the manipulation of O-GlcNAcylation in individual synaptic proteins should reveal hidden aspects of O-GlcNAcylated synaptic proteins as modulators of synaptic transmission.
Topics: Humans; Protein Processing, Post-Translational; Synaptic Transmission; Proteins; Neurons; Diabetes Mellitus
PubMed: 38167470
DOI: 10.1186/s13041-023-01072-4